Vascular endothelial senescence: Exploring current and future diagnostic and therapeutic potential

Age-related endothelial dysfunction is a significant contributor to cardiovascular diseases (CVDs). It is characterized by a state of vasoconstriction, an elevated proinflammatory profile, and higher susceptibility to thrombotic events. Endothelial dysfunction can be attributed to endothelial senescence, contributing to many CVDs like stroke, dementia, atherosclerosis, and many others. The geroscience hypothesis suggests that aging is a driving factor for many comorbid disorders. Therefore, targeting the factors that modulate age could slow down or even prevent these diseases. In their review, Han and Kim discuss the changes observed in vascular senescence, how it contributes to diseases, and cover diagnostics and senotherapeutics.

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Regarding endothelial senescence pathways, the authors mentioned several triggering factors behind this phenomenon. Examples of factors driving the process include:

• Oxidative stress
• Oncogenic activation
• Telomere shortening
• DNA damage
• Mitochondrial dysfunction  

The authors highlighted that the aging process affects mitochondrial function, morphology, and composition. These changes result in a decreased capacity to handle oxidative stress resulting from various processes within the mitochondria. The outcome is an accumulation of reactive oxygen species, damaging DNA and causing telomere attrition. In addition, there is an activation of senescence pathways, resulting in the production of various chemokines, cytokines, and other factors that promote endothelial dysfunction.

Regarding endothelial senescence detection, Han and Kim mentioned several techniques to identify senescent cells. One of the methods is SA-β-gal staining, which assesses the activity of a lysosomal enzyme called beta-galactosidase. The latter enzyme has been detected in several aged tissue samples, including those from the retina and coronary arteries. The other biomarkers mentioned by the researchers were cyclin-dependent kinase inhibitors and telomere length, which have been found to correlate with CVDs. For example, shorter telomere length was associated with worse CVD outcomes and vice versa. They also mentioned the potential of liquid biopsies in advancing the detection of senescent cells.

As for therapeutic opportunities, Kim and Han highlighted several senotherapeutic options. They revealed that senolytics work by inducing apoptosis in senescent cells through activating specific pathways, which have been proven in preclinical settings. They listed several senolytics, like quercetin, dasatinib, and fisetin, and mentioned how these agents are being utilized in clinical studies that explore their potential in Alzheimer's disease, coronary artery disease, and even in healthy participants as protective agents. In addition, they discussed several senomorphics, which are molecules that suppress senescent cells but do not remove them. They included several examples of senomorphics, such as rapamycin, metformin, resveratrol, and others.

The authors concluded that senotherapeutics and diagnostics used in assessing endothelial senescence represent promising areas that could help to understand better and fight age-related ailments. They emphasized that using such therapeutic agents halts not only age-associated deterioration but also improves cardiovascular function and health outcomes for the general population. Further research is needed to precisely map the mechanisms underlying endothelial senescence and explore their potential as target therapeutic agents.

Source: Han, Y., Kim, S.Y. Endothelial senescence in vascular diseases: current understanding and future opportunities in senotherapeutics. Exp Mol Med (2023). https://doi.org/10.1038/s12276-022-00906-w

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